ABSTRACT Pancreatic cancer is almost uniformly lethal, with a five-year survival rate of less than 6%. Over the past 30 years, minimal progress has been made to curb mortality rates and the majority of novel treatment options entering clinical trials have failed. The reason for this is two-fold. First, late-stage diagnosis leads to a large patient population with locally advanced or metastatic diseases, preventing curative local treatment. Second, the aggressive microenvironment of pancreatic tumors hinders drug delivery and promotes immune evasion. This microenvironment is characterized by dense stroma that block access to the tumor parenchyma. Additionally, it houses an abundance of immunosuppressive cell types, encouraging tumor evasion from immune destruction. These aspects contribute to pancreatic cancer's distinct resistance to chemotherapy as well as new immunotherapeutic strategies. Herein, we propose a non-invasive and image-guided approach to overcome these barriers. Ultrasound-stimulated contrast agents will be used to transiently increase the permeability of tumor associated vasculature and stroma via sonoporation. This will (1) allow for enhanced intra-tumoral delivery of immune checkpoint inhibitors and (2) alter the tumor's immune microenvironment through elevated infiltration and activation of anti-tumor immune effector cells, helping to overcome the imbalance of immunosuppressive cell types. We believe that our use of novel and nanometer-sized phase- change contrast agents (PCCAs) will allow for improved sonoporation efficiency compared to standard microbubbles. PCCAs offer the unique potential to infiltrate solid tumors and permeabilize extravascular stromal barriers, which will in turn promote deep diffusion of therapeutic molecules. Ultimately, we anticipate that this strategy will produce a robust anti-tumor immune response that may synergize with currently available immunotherapies, leading to tumor regression and prolonged survival in an orthotopic murine model of pancreatic cancer.